1. Volume 81, Issue 6, Pages 559-567 (March 2012)
Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid 
Bojan Jelaković, Sandra Karanović, Ivana Vuković-Lela, Frederick Miller, Karen L. Edwards, Jovan Nikolić, Karla Tomić, Neda Slade, Branko Brdar, Robert J. Turesky, Želimir Stipančić, Damir Dittrich, Arthur P. Grollman, Kathleen G. Dickman 
Kidney International 
Volume 81, Issue 6, Pages (March 2012)
DOI: /ki
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2. Figure 1
Prevalence of biomarkers of aristolochic acid (AA) exposure and TP53 mutations in cases of upper urinary tract cancers (UUCs) from the endemic villages/regions in Bosnia, Croatia, and Serbia. Aristolactam (AL)-DNA adducts, produced during intracellular nitroreduction of AA, were measured in renal cortex by a 32P-postlabeling-polyacrylamide gel electrophoresis (PAGE) assay.43 Specific mutations in the tumor-suppressor gene TP53 were identified in UUC samples using p53 AmpliChip technology. A:T → T:A transversions (A>T) are the dominant TP53 mutations associated with AA exposure in UUC.16 Tumor DNA was not available for analysis for four cases. Error bars denote 95% confidence intervals for each value. Cortical adducts and tumor TP53 mutations were not detected in DNA samples obtained from nonendemic cases (n=10; data not shown).
Kidney International  , DOI: ( /ki )
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3. Figure 2
Mass spectrometric characterization of DNA-aristolactam (AL) adducts in the renal cortex. (a) Reconstructed ion chromatogram of the liquid chromatography electrospray ionization/multistage mass spectrometry (LC-ESI/MS/MS3) analysis of deoxyadenosine (dA)-AL adducts. (a) Calf thymus DNA served as the negative control and was spiked with the internal standard [15N3]-dA-AL-II at a level of 5 adducts per 108 DNA bases and (b) DNA sample from a upper urinary tract cancer (UUC) subject from Croatia, the level of the [15N3]-dA-AL-II internal standard was 4.2 adducts per 108 DNA bases. The chromatograms for dA-AL-I, dA-AL-II, and [15N3]-dA-AL-II were reconstructed with the four principal fragment ions observed in the spectra of the multistage (MS3) scan mode. The level of dA-AL-I was estimated at 1.5 adducts/108 bases (based on total ion counts of dA-AL-I to [15N3]-dA-AL-II total ion counts). (c) The product ion spectra of the protonated base adduct [BH2]+ for synthetic dA-AL-I (lower panel) and the DNA adduct found in the human renal cortex (upper panel).
Kidney International  , DOI: ( /ki )
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4. Figure 3
Distribution of estimated glomerular filtration rate (eGFR) values, calculated with the Modification of Diet in Renal Disease (MDRD) formula, among upper urinary tract cancer (UUC) cases from endemic and nonendemic villages. Values corresponding to chronic kidney disease (CKD) stages ≥3 are shaded in yellow. Red lines indicate the mean±s.e.m. of each cohort.
Kidney International  , DOI: ( /ki )
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5. Figure 4
Histopathology of renal cortex from three upper urinary tract cancer (UUC) subjects with features highly consistent with endemic (Balkan) nephropathy (EN). Case 1: (a) trichrome- and (b) hematoxylin and eosin (H&E)-stained sections of renal cortex. (a) Fibrosis is patchy and areas of unaffected tubules are noted in this EN case. Involvement of the labyrinth is evident in this area from a subcapsular zone, but the gradient of fibrosis can just be appreciated. (b) Moderately advanced EN with substantial tubular atrophy and extensive interstitial fibrosis. There is little inflammation. Cortical collecting ducts are seen in the upper center field. Glomeruli are relatively intact. Case 2: (c) trichrome- and (d) H&E-stained sections of renal cortex. (c) Advanced classic EN with relative glomerular preservation, profound tubular atrophy, and a gradient from superficial (top of image) to deep cortex of extensive interstitial fibrosis. (d) Typical cortex in advanced EN. The most striking alteration is an almost complete atrophy of proximal tubules. There is almost no inflammation. The glomeruli are preserved but show ischemic change (simplification and condensation). An arteriole in the bottom of the image shows nonspecific sclerotic changes. (e) Significant vascular disease involving an interlobular artery is evident in case 3 (H&E). Vasculopathy is very common in EN and has no distinguishing features. Note the adjacent atrophy of proximal convoluted tubules (arrow). DNA-aristolactam adducts were detected in renal cortex for all three cases. The estimated glomerular filtration rate (eGFR) values (ml/min per 1.73m2) were 61 (case 1), 5 (case 2), and 35 (case 3).
Kidney International  , DOI: ( /ki )
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